Abstract
Aberrant glycosylation, a common feature associated with malignancy, has been implicated in important events during cancer progression. Our understanding of the role of glycans in cancer has grown exponentially in the last few years, concurrent with important advances in glycomics and glycoproteomic technologies, paving the way for the validation of a number of glycan structures as potential glycobiomarkers. However, the molecular bases underlying cancer-associated glycan modifications are still far from understood. Glycans exhibit a natural heterogeneity, crucial for their diverse functional roles as specific carriers of biologically relevant information. This information is decoded by families of proteins named lectins, including sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), C-type lectin receptors (CLRs), and galectins. Siglecs are primarily expressed on the surface of immune cells and differentially control innate and adaptive immune responses. Among CLRs, selectins are a family of cell adhesion molecules that mediate interactions between cancer cells and platelets, leukocytes, and endothelial cells, thus facilitating tumor cell invasion and metastasis. Galectins, a family of soluble proteins that bind β-galactoside-containing glycans, have been implicated in diverse events associated with cancer biology such as apoptosis, homotypic cell aggregation, angiogenesis, cell migration, and tumor-immune escape. Consequently, individual members of these lectin families have become promising targets for the design of novel anticancer therapies. During the past decade, a number of inhibitors of lectin–glycan interactions have been developed including small-molecule inhibitors, multivalent saccharide ligands, and more recently peptides and peptidomimetics have offered alternatives for tackling tumor progression. In this article, we review the current status of the discovery and development of chemical lectin inhibitors and discuss novel strategies to limit cancer progression by targeting lectin–glycan interactions.
Highlights
DECIPHERING THE “GLYCO-CODE” IN CANCERCancer is a leading cause of death worldwide and represents one of the biggest challenges faced by medicine
We focus on therapeutic strategies, based on chemical inhibition of three different lectin families, namely sialic acid-binding immunoglobulin (Ig)-like lectins, C-type lectin receptors (CLRs), and galectins, which play relevant roles in cancer (Figure 2)
Tsuboi et al described a new mechanism of tumor escape involving Gal-3 and natural killer (NK) cells in bladder cancer [83]; the authors demonstrated that overexpression of core 2 β(1→6)-N-acetylglucosaminyl transferase 1 (C2GnT1), a glycosyltransferase responsible of generating branched core-2 O-glycans that can be elongated with poly-N-acetyllactosamine (LacNAc) sequences, negatively controls the activity of tumorassociated major histocompatibility complex class I-related chain A (MICA)
Summary
Cancer is a leading cause of death worldwide and represents one of the biggest challenges faced by medicine. Tsuboi et al described a new mechanism of tumor escape involving Gal-3 and NK cells in bladder cancer [83]; the authors demonstrated that overexpression of core 2 β(1→6)-N-acetylglucosaminyl transferase 1 (C2GnT1), a glycosyltransferase responsible of generating branched core-2 O-glycans that can be elongated with poly-N-acetyllactosamine (LacNAc) sequences, negatively controls the activity of tumorassociated major histocompatibility complex class I-related chain A (MICA). In an attempt to disrupt Siglec-7–GD3 interactions as a potential cancer therapeutic strategy, Attrill et al described the design of sialic acid derivatives as inhibitors of Siglec-7 signaling [103] One of these ligands, oxamido-Neu5Ac [8, Table 2, methyl α-9-(amino-oxalyl-amino)-9-deoxy-Neu5Ac] exhibited a twofold decrease in the IC50 value (1.6 mM) for inhibition of Siglec-7 in vitro, compared to the canonical ligand methyl-α-Neu5Ac (>3.0 mM) [103]. Iurisci et al reported the use of allyl-lactoside (13, Table 3) as ligand of Gal-1 and TABLE 2 | Anti-siglec agents described in this review
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